Abstract

Glioblastoma is one of the most common primary brain tumors in adults. The current treatment strategies failed to achieve satisfactory outcomes. Anti-vascular endothelial growth factor (anti-VEGF) agents have been proposed to enhance the survival and quality of life in these patients. To investigate this, different databases were searched in addition to hand searching. Relevant studies were screened and only ten randomized controlled trials (RCTs) met the eligibility criteria; six of them were considered for meta-analysis. Eligible RCTs were assessed regarding risk of bias using the Cochrane tool. Relevant data were extracted and meta-analysis was conducted using the random effects model analysis on RevMan software. One thousand seventy-eight patients in the anti-VEGF group and 946 patients in the control group were available for analysis. No statistically significant improvement in the overall survival (OS) was detected for anti-VEGF (OR 0.87, 95% CI 0.7–1.09, p = 0.23) or bevacizumab subgroup (OR 0.84, 95% CI 0.65–1.08, p = 0.17) compared to standard therapy alone. However, the progression-free survival (PFS) showed a significant improvement with both anti-VEGF (OR 0.76, 95% CI 0.65–0.89, p = 0.0007) and bevacizumab subgroup (OR 0.75, 95% CI 0.65–0.87, p = 0.0001). In conclusion, anti-VEGF agents can improve the PFS but not OS in glioblastoma patients. The current evidence is not satisfactory to declare a new therapeutic line. Further RCTs with sharply determined outcomes and assessment methods are required.

Keywords

Anti-VEGF Bevacizumab Glioblastoma Survival Meta-analysis

Abbreviations

OS

overall survival

PFS

progression-free survival

VEGF

vascular endothelial growth factor

Introduction

Among the primary brain tumors in adults, the incidence of glioma is the highest, compromising nearly 15% of those tumors [1]. According to the World Health Organization (WHO), glioma is scaled over four grades: grades I and II represent low-grade gliomas (with a good prognosis), whereas grades III and IV represent high-grade gliomas (with worse prognosis). Grade IV glioma is known as glioblastoma (GBM) and carries the worst prognosis [2]. The current standard therapy includes maximal surgical debulking, radiotherapy, and chemotherapy (either concurrent or adjuvant) with temozolomide, a DNA alkylating agent [3]. Many clinical and molecular factors intersect to determine the prognosis. However, only 5% of these patients attain a 5-year survival [1]. The latter fact promoted efforts to explore new lines for treatment aiming at achieving better outcomes.

Several agents have been investigated for GBM therapy. These tumors are highly vascular owing to a protein known as vascular endothelial growth factor (VEGF), which promotes new blood vessel formation, enhancing the tumor growth. This pattern of growth and spread of tumors have been established in animal and clinical settings. Given this fact, anti-angiogenesis therapy has become a target for many trials. Anti-vascular endothelial growth factors (anti-VEGF) have shown to be the most promising agents [4, 5].

Anti-VEGF agents have been proposed to inhibit the formation of new blood vessels, hereby depriving the tumor from its essential nutrients and oxygen. Therefore, these agents are proposed to inhibit the tumor growth and spread. Nevertheless, the involved mechanisms have been revealed to be more complex. It has been reported that anti-VEGF agents can enhance the efficacy of the chemotherapy and radiotherapy through their “normalizing” effects on the blood vessels [6, 7]. Many trials investigated the efficacy of anti-VEGF agents in GBM patients [8, 9, 10, 11, 12, 13, 14, 15, 16, 17]; some reported better clinical, radiological, and molecular outcomes when anti-VEGF agents have been added [12, 13]. On the other hand, other studies report drawbacks of these agents on the quality of life with no significant survival improvement [8, 10, 11]. That is why bevacizumab (one of anti-VEGF agents) was approved in the USA and Japan for glioblastoma where it is still experimental in Europe.

The use of anti-VEGF in the treatment of glioblastoma is controversial. In this review, we aim to get evidence regarding the effectiveness and safety of anti-VEGF agents as adjunctive therapy for glioma.

Methods

Criteria for considering studies for this review

Types of studies

We considered any randomized controlled trials (RCTs) involving any anti-VEGF agent in one arm, as a first or second line, in glioma patients of any grade, either newly diagnosed or recurrent. We considered RCTs where the comparison was standard therapy + anti-VEGF versus standard therapy + placebo or the comparison was standard therapy + two anti-VEGF agents versus standard therapy + one anti-VEGF. This was supposed to get the overall effect of anti-VEGF in glioma. Only RCTs available in full texts were considered for this review whereas conference abstracts were excluded.

Types of participants

The types of participants were patients with GBM of any grade.

Types of interventions

The types of interventions were anti-VEGF for GBM patients of any grade. Different anti-VEGF agents are considered either direct or indirect ones. Direct agents include bevacizumab, ranibizumab, and aflibercept, while indirect agents included cediranib.

Types of outcome measures

RCTs were considered if one of these outcomes was reported. The primary outcome was the overall survival (OS) rate, and the secondary outcomes included progression-free survival (PFS), adverse events reported in the trials, and quality of life, if assessed through a validated method.

Moreover, hand searching of the reference lists of the relevant studies was conducted. No language restrictions were applied.

Data collection

Search results were screened for de-duplication. After that, title/abstract screening was performed. Full texts of relevant studies were obtained and screened based upon the pre-specified eligibility criteria. Each eligible trial was reviewed to extract all relevant data. For studies with multiple reports, the last one was considered.

Assessment of risk of bias in included studies

Using the Cochrane’s tool for assessing risk of bias, each trial was assessed in the six domains: sequence generation, allocation concealment, blinding, attrition bias, selective outcome reporting, and other sources of bias. Each trial was labeled as high, low, or unclear in each domain with the rationale for each decision.

Data synthesis

Review manager 5.3 was used to perform the statistical analysis and generate figures. The OS and PFS outcomes were reported as odds ratio (OR) with 95% confidence interval (CI). Heterogeneity was assessed using the chi-square and I-square tests, and the random effects model was adopted for analysis when the chi-square p value was less than 0.1. Otherwise, we used the fixed effects model.

Results

Literature search results

Searching different databases yielded 571 papers with additional 19 papers were retrieved through hand searching of references’ list of relevant studies. After de-duplication, 395 papers were subjected for title/abstract screening. The full texts of 29 papers were thoroughly screened for eligibility criteria; among them, 10 RCTs matched the pre-specified criteria and were included in qualitative analysis. For quantitative analysis, only 6 RCTs were eligible (Fig. 1).

Characteristics of included studies

All ten RCTs included GBM patients with at least one arm containing anti-VEGF agent(s). Six trials were designed as standard therapy + placebo versus standard therapy + anti-VEGF [8, 9, 10, 11, 12, 13]. The other four trials were excluded from quantitative analysis [14, 15, 16, 17] because both comparison arms contained anti-VEGF agents. This yielded 2024 patients: 1078 in the anti-VEGF group and 946 in the control group, available for quantitative analysis (Table 1). All the studies included were two-arm trials except for three that included three arms [8, 9, 13]. Bevacizumab was the most commonly used agent (in eight out of ten trials). One trial [13] used cediranib and the last trial [8] used cilengitide. PFS was the primary outcome in five trials, while in another two trials [10, 14], PFS and OS were co-primary endpoints. Secondary outcomes were variable among the studies; however, safety profile (or adverse events) and OS were evaluated in all studies.

Risk of bias assessment

Each study was assessed regarding the six domains of bias, using the Cochrane tool for risk of bias assessment. Only one trial (Batchelor 2013) was judged to be of low risk in all domains. Another trial (Taal 2014) was labeled as of high risk in more than two domains. Regarding selection bias, all RCTs were of low risk for sequence generation except for three trials [15, 16, 17] that were unclear concerning the randomization method. Moreover, in the allocation concealment domain, only five RCTS were at low risk, while the other five studies did not clarify how participants’ allocation for study arms was concealed. Figure 2 summarizes the risk of bias of the included studies.

Outcomes

A.

Survival outcomes: Regarding OS, 1078 patients in the anti-VEGF group and 946 patients in the control group were available for analysis. The pooled OR was 0.87 with 95% CI 0.7–1.09, favoring anti-VEGF + standard therapy. However, no statistically significant difference was detected among the two groups (p = 0.23). One thousand thirty-four patients in the anti-VEGF group and 867 patients in the control group were available for analysis of PFS. The pooled OR was 0.76 with 95% CI 0.65–0.89, significantly favoring the anti-VEGF + standard therapy over the standard therapy (p = 0.00007). Figures 3 and 4 illustrate the forest plots of this comparison (standard therapy + anti-VEGF versus standard therapy alone) for OS and PFS, respectively.

Quality of life: Regarding the QOL, only two studies used validated methods to assess QOL changes. The study by Chinot et al. 2014 (AVAglio study) reported a significant improvement in QOL with anti-VEGF agents, as assessed through global health status and Karnofsky health score. All patients in the AVAglio study filled the questionnaire [11]. In contrast, the study by Gilbert et al. (2014) reported deterioration in QOL and cognitive functions with anti-VEGF agents [10].

C.

Adverse events: Adverse events reported in different trials were similar. Major adverse events (grade ≥ 3) included wound complications (1.6 to 3.3%), thromboembolism (3.1 to 11.2%), and hypertension (4.2 to 26%). Table 2 illustrates the major AEs in the included trials. However, meta-analysis was not applicable.

Discussion

Glioma is a major challenge for many reasons. First, it is the most prevalent primary brain neoplasm, representing nearly 15% of this category. Second, according to its site, it may have different presentations [18, 19, 20]. Moreover, its poor prognosis (especially with grades III and IV) poses another disappointing fact despite the current therapeutic options (surgery, chemotherapy, and radiotherapy). With a 5-year survival rate of only 5%, the need for new treatment lines is pressing [1].

Different therapeutic strategies have been investigated for GBM [21, 22, 23, 24]. Given the fact that glioma is highly vascular, anti-angiogenesis therapy has been thought to be the breakthrough in glioma therapy. Building upon provisional results in many solid tumors, different anti-angiogenic agents have been investigated as adjuvant lines of treatment to the standard one. Many mechanisms are involved, but inhibition of new blood vessels formation is the cornerstone one. Depriving the tumor from its oxygen and nutrients supply can limit its growth and spread. Anti-VEGF agents can be classified as direct, indirect, or mixed depending on how they work. Multiple agents are available including bevacizumab, ranibizumab, aflibercept, cediranib, and cilengitide [4, 6].

Many RCTs have been conducted to investigate the safety and efficacy of anti-VEGF agents in GBMs. While improved survival has been reported by some authors [12], deterioration of life quality and significant toxic effects are highlighted in other studies [8, 10, 11]. An evidence-based decision is essential for clinical setting. In this systematic review, different databases were searched for relevant studies with no language or period limitations. Our search retrieved ten RCTs with anti-VEGF in one arm at least.

Summary of the main outcomes

In this review, no statistically significant improvement in OS among the comparison groups (OR = 0.87 with 95% CI 0.7–1.09, p = 0.23) was detected. However, a statistically significant difference could be detected in PFS (OR = 0.76 with 95% CI 0.65–0.89 and p value = 0.00007). Similar results were found with the subgroup analysis considering bevacizumab only regarding both OS (OR 0.84, 95% CI 0.65–1.08, p = 0.17) and PFS (OR 0.75, 95% CI 0.65–0.87, p = 0.0001). The improvement in PFS may be explained by a true effect of anti-VEGF agents. However, the imaging modality used is biased and cannot differentiate between true and pseudo-response.

These results are in accordance with Khasraw et al. 2014, who reported no significant improvement in OS, but significant one in PFS. While we only considered full-text articles, Khasraw et al. 2014 included data from abstracts only. Abstracts are insufficient to build upon even if provided certain outcomes’ data [25]. We cannot trust how studies were conducted and Khasraw did not explain how they verified the extracted data. Yang et al. 2016 published similar results regarding both OS and PFS. However, this systematic review considered only bevacizumab combined with chemotherapy for glioma, narrowing its scope in analysis [26].

The included RCTs have certain limitations to be considered. Four out of ten trials are open-label with a high risk of bias in the blinding domain. Batchelor 2013, Friedman 2009, and Cloughesy 2017 were restricted for recurrent glioma, while Taal 2014 investigated anti-VEGF agents at the first progression of the tumor. The included RCTs used different time points for outcome assessment, another weak point to highlight. Another significant limitation to consider is the method of outcome assessment; many trials relied upon radiological assessment of the tumor progression. This ignored the concepts of “pseudo-progression” and “pseudo-response” on MRI. The Response Assessment in Neuro-Oncology Criteria (RANO) criteria are reliable and should be considered in future RCTs [27]. Regarding associated adverse events and toxicities, future trials should consider adding possible protective agents to these chemotherapeutic regimens [28].

Conclusion

This review showed no significant difference in OS with anti-VEGF added to standard therapy versus standard therapy alone in GBM patients. The improvement in PFS is a promising result to investigate, but the assessment criteria must be reliable and unified. Larger, well-designed, multicenter, patient-centered RCTs are required.

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Appendix 1

(((randomized controlled trial[pt] OR controlled clinical trial[pt]) OR(randomized OR randomized OR randomly OR placebo[tiab]) OR (trial[ti]) OR (“Clinical Trials as Topic”[MeSH Major Topic])) AND ((Glioblastoma[MeSH Terms]) OR Glioma*[Title/Abstract])) AND (((((Anti vascular endothelial growth factor [Title/Abstract]) OR (anti-VEGF[Title/Abstract]) OR (Bevacizumab*[Title/Abstract]) OR (ranibizumab*[Title/Abstract]) OR (cediranib*[Title/Abstract]))))